the h19 non-coding rna is essential for human tumor growth段h19非编码rna对人类肿瘤的生长至关重要.pdf

The H19 Non-Coding RNA Is Essential for Human Tumor Growth 1 1 1 1 1 1 2 Imad J. Matouk , Nathan DeGroot , Shaul Mezan , Suhail Ayesh , Rasha Abu-lail , Abraham Hochberg , Eithan Galun * 1 Department of Biological Chemistry, Institute of Life Sciences, Hebrew University, Jerusalem, Israel, 2 Goldyne Savad Institute of Gene Therapy, Hadassah Hebrew University Hospital, Jerusalem, Israel Background. Mutations and epigenetic aberrant signaling of growth factors pathways contribute to carcinogenesis. Recent studies reveal that non-coding RNAs are controllers of gene expression. H19 is an imprinted gene that demonstrates maternal monoallelic expression without a protein product; although its expression is shut off in most tissues postnatally, it is re- activated during adult tissue regeneration and tumorigenesis. Moreover, H19 is highly expressed in liver metastasis derived from a range of carcinomas. The objective of this study is to explore the role of H19 in carcinogenesis, and to determine its identification as an anti-tumor target. Methodology/ Principle Findings. By controlling oxygen pressure during tumor cell growth and H19 expression levels, we investigated the role of H19 expression in vitro and in vivo in hepatocellular (HCC) and bladder carcinoma. Hypoxia upregulates the level of H19 RNA. Ablations of tumorigenicity of HCC and bladder carcinomas in vivo are seen by H19 knockdown which also significantly abrogates anchorage-independent growth after hypoxia recovery, while ectopic H19 expression enhances tumorigenic potential of carcinoma cells in vivo. Knocking-down H19 message in hypoxic stress severely diminishes p57kip2 induction. We identified a number of potential downstream targets of H19 RNA, including angiogenin and FGF18. Conclusions. H19 RNA harbor